Secondary hyperparathyroidism is a common and severe complication of chronic renal failure (CRF) resulting in renal osteodystrophy, hypertension, metabolic acidosis, and contributing to cardiac disease. Hyperphosphatemia due to decreased renal phosphate excretion is thought to contribute to secondary hyperparathyroidism in patients with chronic renal insufficiency. Recently, it has been established that decreasing the phosphate load can reduce secondary hyperparathyroidism and possibly preserve renal function.
In mammals, intestinal phosphate absorption occurs at the brush border membrane in the proximal intestine (duodenum and jejunum). Phosphate absorption has an active component and a passive component. Active uptake of phosphate is coupled to Na+ uptake down its electrochemical potential gradient by the Na+/phosphate cotransporter. The active component of phosphate absorption is regulated by dietary phosphorus and serum 1,25 dihydroxyvitamin D3. Changes in dietary phosphorus have been reported to alter expression of NaPi II b in the intestine. Na+-independent phosphate uptake occurs by an unknown mechanism down its electrochemical potential gradient. The mechanism of phosphate transport across the intestinal basolateral membrane has not been defined
Chalcones are a class of aromatic ketones with important biological activity and their effect on membrane transport is well known. Phloridzin, a member of the chalcones, is a potent inhibitor of the renal and intestinal brush border membrane Na+/glucose cotransporters. The aglucone of phloridzin, phloretin, inhibits a variety of membrane transporters including Band 3 (AE-1, 9, 10) and the facilitated diffusion glucose carrier (GLUT-4, 9, 14). A phosphorylated phloretin derivative, 2′-PP, has been shown to be a potent inhibitor of the intestinal Na+/phosphate cotransporter but not the primary renal proximal tubule Na+/phosphate cotransporter. The major limitation of 2′-PP for the treatment of hyperphosphatemia is that it is a phosphate ester, and therefore, it is degraded by phosphatases, including the intestinal apical membrane phosphatase, alkaline phosphatase.
Thus, new or improved agents which inhibit intestinal apical membrane Na+-mediated phosphate co-transport are continually needed for developing new and more effective pharmaceuticals that are aimed at the treatment of secondary hyperparathyroidism caused by CRF and resulting in renal osteodystrophy, hypertension, metabolic acidosis, and contributing to cardiac disease. 2′-FPP which is 30 times more potent than 2′-PP and is also more stable to esterases represents a major advance and improvement over 2′-PP well known to be efficacious in the treatment of CRF. The compounds, compositions and methods described herein are directed toward these needs and other ends.